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. Author manuscript; available in PMC: 2015 Nov 1.
Published in final edited form as: Curr Opin Nephrol Hypertens. 2014 Nov;23(6):578–585. doi: 10.1097/MNH.0000000000000067

Is Left Ventricular Hypertrophy a Modifiable Risk Factor in ESRD

David Charytan 1
PMCID: PMC4266593  NIHMSID: NIHMS638712  PMID: 25295959

Abstract

Purpose of Review

Left ventricular hypertrophy (LVH) is common in ESRD and has been advocated as a therapeutic target. We review considerations for targeting LVH as a modifiable risk factor in ESRD.

Recent Findings

Pathologic myocardial changes underlying LVH provide an ideal substrate for the spread of arrhythmia and may be key contributors to the occurrence of sudden death in ESRD. LVH is present in 68-89% of incident hemodialysis patients and is frequently progressive, although regression is observed in a minority of patients. Higher degrees of baseline LVH as well as greater increases in left ventricular mass index over time are associated with decreased survival, but whether these association are causal remains uncertain. Several interventions including angiotensin blockade and frequent dialysis can reduce left ventricular mass index but whether the associated decrease in left ventricular mass index is associated with improves survival has not been definitively demonstrated.

Summary

LVH is a highly prevalent and reversible risk factor which holds promise as a novel therapeutic target in ESRD. Interventional trials are needed to provide additional evidence that LVH regression improves survival before prevention and reversal of LVH can be definitively adopted as a therapeutic paradigm in ESRD.

Keywords: LVH, ESRD, Cardiovascular, Sudden cardiovascular death

Introduction

Mortality in dialysis dependent end stage renal disease (ESRD) remains high with only 52% of hemodialysis (HD) and 61% of peritoneal dialysis (PD) patients alive 3 years after initiation1. The high mortality remains incompletely explained but it is dramatically higher than for individuals with preserved renal function and similar degrees of comorbidity. To wit, age, sex and comorbidity adjusted mortality rates were 241 per 1000 patient-years in the prevalent ESRD population in 2011 compared with adjusted rates of 109 and 71 per 1000 patient-years among general Medicare patients with cancer or diabetes, respectively1.

Cardiovascular disease (CVD) is an important contributor and accounts for 42.0% of all fatalities1. However, in contrast to other populations, myocardial infarction accounts for only a minority of CV deaths with the majority attributed to sudden cardiac death (SCD)—an event that occurs at a rate of 49/1000 patient-years among HD patient and 36/1000-patient years among individuals on PD.

This has motivated a tremendous interest in identifying therapeutic strategies with the potential to improve survival, and prevention of CV death, unsurprisingly, has become a major target. Standard CVD therapies, particularly those targeting coronary atherosclerosis, have thus far not provided satisfactory results. To wit, three large trials randomizing more than 7000 dialysis patients to statins or placebo failed to significantly impact mortality despite the consistently beneficial results of statins in other settings2-4. In light of the unique pathophysiology and epidemiology of CVD in CKD5 and disproportionate risks of SCD compared with myocardial infarction/coronary death, the disappointing results of anti-atherosclerotic therapy (with statins) in ESRD suggests that future efforts to improve survival should focus SCD prevention. In this manuscript we review the role of left ventricular hypertrophy (LVH) as a contributor to SCD and therapeutic target in ESRD.

Etiology of Sudden Cardiac Death in ESRD

In experimental models, uremia inhibits compensatory angiogenesis in response to hypoxia6. Experimental CKD is characterized by decreased myocardial capillary density, reduced ischemia tolerance, and increased infarct size after coronary artery ligation6-11. These changes are accompanied by LVH with accumulation of interstitial collagens and myocardial fibrosis that are at least partly independent of hypertension7-9, 12. Although human data is more limited, similar changes have been observed in a few studies. In a classic study by Ritz and Amman, for example, ESRD patients with LVH (but without overt coronary disease) demonstrated myocte hypertrophy, loss of myocardial capillaries, increased interstitial fibrosis, and a reduced capillary to myocyte ratio compared with patients with preserved renal function13.

Clinical surrogates for these myocardial changes are consistent with the experimental and pathologic studies. Myocardial coronary flow reserve--a measure of microvascular supply and function—declines in parallel with glomerular filtration14-17, while coronary collateral vessels—whose presence reduces the risk of death in CAD18, 19— are 41% less abundant in individuals mild-moderate CKD than patients without CKD20. Similarly Left ventricular (LV) mass (see below), diastolic function and late gadolinium enhancement (a marker of myocardial scar/fibrosis) increase dramatically as GFR declines and are associated with risk of death21-28.

The combination of increased myocyte size, interstitial collagen content, and microvascular rarefaction increases intra-capillary distances and capillary to cardiomyocyte distances9, 13. These changes inhibit basal diffusion of oxygen and glucose from capillary to myocyte and reduce ischemia tolerance thereby heightening the risk of myocyte necrosis when coronary blood flow is reduced. Increased myocyte size, interstitial fibrosis and larger distances between adjacent myocytes lead to concomitant disruption of myocardial electrical pathways. The combination lowers the threshold for the propagation of fatal arrhythmias and is likely a key mechanism underlying the high incidence of SCD in dialysis-dependent ESRD. Thus, LVH with pathologic mismatching of myocyte to capillary supply stands out as critical and potentially modifiable risk factor for CV death in dialysis dependent ESRD.

Etiology of Left Ventricular Hypertrophy

Pressure overload—either from hypertension or decreased vascular compliance (e.g. from cardiac calcification)—is a major contributor to LVH in ESRD29, 30. Increased preload, makes is similarly important, particularly to the development of eccentric rather than the concentric LVH which characterizes pure pressure overload29, 31. Factors implicated in preload related LVH include anemia32, arterial-venous dialysis accesses with high output33, and salt and volume overload34, 35 (a ubiquitous factor in thrice-weekly maintenance dialysis patients). Finally, numerous circulating and cellular factors—many of which are excessively active in the setting of ESRD—may independently contribute to the development of LVH or modify the associations of preload and afterload with LVH.

The renin-angiotensin-aldosterone system has been recognized as a crucial component in the development of LVH35, 36, and clinical studies are consistent with an important role in the LVH of ESRD37-40. The role of the bone and mineral metabolism axis has been more recently recognized, but emerging evidence is generally consistent with important roles for vitamin D41, parathyroid hormone42, 43, and FGF-2344, 45 in the adverse myocardial remodeling of ESRD. Finally, emerging evidence implicates a host of additional factors such as disordered nitric oxide metabolism46, 47, elevated concentrations of endogenous cardiac glycosides48, and changes in mammalian target of rapamycin (mTOR) pathway signalling49, among other factors, as CKD-specific contributors to adverse cardiac remodeling (Figure 1).

Figure 1. Contributors to Adverse Remodeling of the Left Ventricle in ESRD.

Figure 1

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Factors contributing to capillary dropout and left ventricular hypertrophy in ESRD. HTN-hypertension. LVH-left ventricular hypertrophy. ADMA-asymmetric dimethyl arginine. FGF-23-fibroblast growth factor 23. mTOR-mammalian target of rapamycin.

Prevalence and Progression

LVH is highly prevalent in the dialysis population and was present in nearly 75% of 433 incident patients in a seminal study by Foley in 199550. Similarly, in a smaller study of incident Japanese dialysis patients 68% had LVH51. More recent analyses of the Chronic Renal Insufficiency Cohort and a Japanese inception cohort showed that 79% and 85% of individuals starting dialysis had LVH at the time of initiation52, 53. LVH frequency is also high in prevalent dialysis patients but actually appears to be slightly less common. The incidence of LVH has varied across studies ranging between 36%- 77%54-58 in relatively unselected cohorts of prevalent dialysis patients, but is likely higher among truly unselected populations including individuals with known heart failure or CV disease.

The author is unaware of studies directly comparing the incidence of LVH in similarly defined populations of prevalent and incident hemodialysis patients. However, several studies have examined the progression of ventricular remodeling in the absence of anti-LVH therapy. In an observational study of 161 prevalent dialysis patients without congestive heart failure and with baseline ejection fraction >35%, there was a significant 6.7% in increase of left ventricular mass index (LVMI) over an average 18 month interval between echocardiographic studies. Interestingly, although LVH increased on average, there was a distinct associaoin between baseline LVMI and LVH progression—individuals in the upper quartile of LVMI showed much smaller increases than those with more normal ventricular geometry at baseline59. Conversely, in an older study of 227 PD and HD patients, LVMI decreased in up to 48% of patients between inception and 1-year while increasing or remaining stable in the remainder60. Findings were similar in a study of 111 incident dialysis patients in Korea, 32 of whom had repeat echocardiography ≥6 months after an initial study. Although mean LVMI increased on average from 196 g/m2 to 210 g/m2 (P=0.05), it was stable or decreased in 41% of patients61.

More recently, in a clinical trial enrolling 596 anemic, relatively new (dialysis vintage < 18 months) HD patients without heart failure or ischemic heart disease, progressive LVH was observed regardless of randomized therapy62. LVMI increased from 114 g/m2 at baseline to 121 g/m2 at 24 weeks, 123 g/m2 at 48 weeks and 128 g/m2 at 96 weeks (P<0.001). Despite a mean increase in LVMI, LVH was stable or decreased in 37% of patients.

In summary, LVMI increases substantially in the majority of dialysis patients treated according to the usual standard of care. However, it is clear that an increase in LVMI is not inevitable. A substantial minority of dialysis patients do not experience LVH progression during medium to long-term follow-up, and a minority actually experience substantial LVH regression.

Association of Baseline LVH with Outcomes

It should be noted that the presence of either baseline or progressive LVH is strongly associated with adverse outcomes. It is likely that these studies actually underestimate the likelihood and degree of LVH progression in the dialysis population given a higher likelihood of early death (with subsequent failure to obtain follow-up evaluations of left ventricular structure) in those with the most severe or progressive LVH.

Associations of baseline LVH with survival have been well-studied. Higher LVMI is clearly a risk-factor for mortality, but whether this effect is independently associated with outcomes is less certain. A seminal study of 91 incident dialysis patients beginning therapy between 1983-1987 was one of the earliest to demonstrate an association between baseline LVH and all-cause or CV mortality with adjusted hazard ratios of 2.9 (95% CI: 1.3-6.7) and 2.7 (95% CI: 0.9-8.2), respectively63. Similarly an analysis of 2257 individuals who initiated dialysis between 1996-1997 demonstrated a relative risk of 1.29 (95% CI: 1.07-1.56) for 2-year mortality after adjustment for demographic factors. The risk ratio remained >1.0 but lost significance with further adjustment for prevalent cardiovascular disease64. Similarly in a study of 433 prevalent patients studied in the mid 1980s, higher LVMI at baseline was independently associated with significantly increased late (after 2-years) mortality. However, crude associations with overall mortality during the entire length of follow-up were attenuated in multi-variable models adjusted for demographics, diabetes and the presence of ischemic CV disease65. In a similar vein, in the aforementioned clinical trial of 596 anemic hemodialysis patients62, an association of LVMI with combined CV events and death was present (HR 1.14, 95% CI: 1.10-1.29 for LVMI increments of 21.g/m2) in models adjusting for age and sex, but the association was lost with further adjustment for comorbidities and cardiovascular biomarkers.

A few studies have demonstrated a fully independent association of LVH with all-cause or CV mortality. For example, a recent study of 317 incident patients showed that baseline LVH was associated with a >11-fold increase in the risk of CV death (P=0.02) after adjustment for baseline ejection fraction, age, diabetes, presence of coronary disease, and electrocardiographic parameters66. An analysis of the randomized FOSODIAL trial (fosinopril vs. placebo for 24 months), similarly demonstrated an independent association between LVMI and the risk of subsequent CV events after correction for relevant comorbidities67.

In contrast, a few studies have not found significant associations between LVH and survival. Madsen, studied 109 prevalent hemodialysis patients and found no association between LVH and mortality in either univariate or multi-variable analyses, although there were only 34 deaths during 2-years of follow-up55. Similarly in a study by Satyan of 150 prevalent dialysis patients followed for 2 years (46 deaths), LVMI was not a predictor of mortality54. The lack of an association in these studies may reflect the small sample size, limited number of fatalities, and correction for cardiac biomarkers whose concentration are likely to be correlated with LVMI and may be on the causal pathway between LVH and outcomes. However, a recently published study of 404 incident Japanese hemodialysis actually demonstrated that lower LVMI at baseline was associated with worse all-cause and CV survival in both crude and adjusted analyses. Interestingly, this “reverse epidemiology” was apparent only in patients without pre-dialysis erythropoietin use53.

The meaning of these disparate findings is open to interpretation, but the majority of studies, particularly the better powered ones, have demonstrated strong associations between LVH/LVMI and survival/CV outcomes. Thus, it is reasonable to conclude that the presence of baseline LVH is a strong risk factor for adverse outcomes in dialysis patients. Whether this effect is independent of the association of LVH with other comorbidities such as diabetes, hypertension and duration of dialysis or reflects a direct causal effects, is an issue requiring further study.

LVH Progression and Outcomes

Relatively few studies have assessed associations of change in LVH with outcomes in individuals with ESRD. However, these few studies show consistently strong links between change in left ventricular mass and outcomes. In a seminal study, 227 prevalent dialysis patients underwent baseline echocardiography within 1 year of starting dialysis and repeat echocardiogram one year later. Increased LVMI was strongly associated de novo congestive heart failure in multivariable modles—HR per 20 g/m2 1.3 (95% CI: 1.1-1.5)60. In the CREED study, 173 prevalent dialysis patients without a history of congestive heart failure and ejection fraction >35% were observed with serial echocardioagrams59. There was graded relationship between the rate of increase in LVMI and the risk of death—adjusted HR 3.07 (95% CI: 1.34-7.05) for individuals with rates of LVMI increase above the 75th percentile compared to those below the 25th percentile. Similar associations were observed in an analysis of fatal cardiovascular events. Finally, in a single-center prospective study of 153 incident and prevalent HD patients who underwent multi-factorial intervention of hypertension, anemia and volume overload, each 10% decrease in LVM was independently associated with a significant decrease in the risk of both all-cause (HR 0.78, 95 CI: 0.63-0.92) and CV mortality (HR 0.72, 95% CI: 0.51-0.90)68.

Interventions to Regress LVH

As reviewed above, it is clear that progression of LVH is not inevitable, and that stability or progressive decreases in LVMI occur in a substantial proportion of dialysis patients. This high proportion makes it difficult to assess the efficacy of potential therapeutics for LVH on the basis of non-randomized studies. However, relatively few randomized trials have assessed LVH as a primary outcome measure. A full review of these studies is beyond the scope of this manuscript, but several studies strongly suggest the potential for a variety of interventions to mitigate progression or even reverse established LVH. A brief review of several illustrative studies is presented.

Angiotensin Blockade

A few trials have confirmed the potential of angiotensin blockade to improve LVH in ESRD. In a small trial, 30 chronic HD patients were randomized to losartan, enalapril or amlodipine. At 6 months, LVMI reduction was significantly lower with losartan (-24.7 +/- 3.2%) than with amlodipine (-10.5 +/- 5.2%) or enalapril (-11.2 +/- 4.1%) , despite similar blood pressure reduction69. Although a better response with angiotensin blockers compared to converting enzymes was not observed in another small trial of 33 incident, diabetic hemodialysis patients randomized to enalapril 10 mg daily, losartan 100 mg daily or combination therapy, there was a blood pressure independent benefit of more complete angiotensin blockade. At 1 year, LVH progressively decreased in all 3 groups, but there was an additional 28% reduction in the dual therapy group (P<0.05)70 despite similar blood pressure reduction. A 3rd small trial compared imadpril (2.5 mg daily) with placebo in 30 hemodialysis patients. Despite no significant impact on blood pressure in either group, LVMI was significantly decreased by 18% in the imidapril group but was unchanged in the placebo group (P<0.05)71. Although these studies are small, in total they provide intriguing evidence supporting the potential for angiotensin blockade to regress LVH. Large studies seem warranted on this basis. However, the failure of fosinopril to improve all-cause or CV mortality in a relatively sizeable outcomes trial limits enthusiasm and raises questions about whether the improvement in LV morphology will necessarily translate into better clinical outcomes.72.

Dialysis Frequency

In the Frequent Hemodialysis Network Daily Trial, 245 patients were randomized to 6×/week or 3×/week HD. A nocturnal trial randomized 87 patients to long nocturnal (3×/week) vs. conventional dialysis. Cardiac MRI was performed at baseline and 12 months. LVMI decreased with intervention compared to control in both the daily (-13.1g, 95% CI:-5.0, -21.3) and nocturnal trials(-10.1g, 95% CI: -23.7, 1.8) but the difference achieved significance only in larger, daily trial73. These data demonstrate a clear effect of more frequent dialysis on LVH but leave uncertain whether more frequent dialysis achieves this impact through improved clearance, better control of volume and hypertension or through other, unrecognized mechanisms.

Anemia Management

Multiple studies have examined the impact of exogenous erythropoietin on LVH but few have been randomized. Although a meta-analysis of both randomized and cohort studies suggested a significant impact on LVH in dialysis patients with severe anemia at baseline this effect was observed principally in cohort studies and was not observed in randomized trials74. In the largest randomized studies including 59662 and 14675 hemodialysis patients with moderate anemia, correction to a higher hemoglobin had no significant impact on LVMI. Thus, available data have failed to demonstrate a convincing impact of anemia correction on ventricular geometry despite non-randomized studies suggesting strong associations of anemia or anemia correction and LVH.

Conclusions

Biologic considerations suggest that multiple pathways contribute to development of LVH in ESRD and that LVH is an important mechanism underlying sudden death in dialysis dependent ESRD. It is highly prevalent, frequently progressive, and is clearly a risk factor for CV events and death in this population. Additionally, several trials have demonstrated the potential to modify LVH in dialysis-dependent ESRD using readily available tools or by interfering with well understood physiologic pathways. These considerations demonstrate that LVH is clearly a modifiable risk factor in ESRD.

However, a more appropriate question is whether targeting LVH is now warranted. The answer to this question is less certain. Despite promising results, few trials, mostly of modest size, have targeted LVH in ESRD. Important questions remain about the ideal therapies for LVH and optimal populations for their application. It remains uncertain whether LVH is an independent risk factor in ESRD or whether the association primarily reflects the association of LVH with prevalent conditions such as hypertension and volume overload--in which case these factors might be the better targets. Additionally, associations of LVH improvement with clinical outcomes have not been widely studied. Whether therapeutic improvement in LVMI will reduce mortality and whether that improvement will be equivalent for similar degrees of LVMI change across therapies with divergent mechanisms of action is unknown (additional considerations in Table 1). Given these considerations LVH improvement cannot yet be considered a reliable surrogate outcome measure for use in the context of ESRD.

Table 1.

Considerations for LVH as a Therapeutic Target in ESRD
Pro
 High prevalence
 Strong (univariate) associates of baseline LVH with all-cause mortality and CV events
 Independent associations of LVMI progression with survival
 Treatable risk factor—demonstrated reversibility in randomized angiotensin blockade studies and frequent dialysis studies
 Multiple underlying pathways provide multiple targets for therapeutic intervention
 Easy to measure-echocardiography is non-invasive and widely available
Con
 Uncertain whether an independent/causal risk factor
 LVH not established as a reliable surrogate outcome measure in ESRD—studies demonstrating associations of randomized change in LVMI with outcomes are lacking
 Optimal therapeutic maneuvers and targets (e.g. goal blood pressure) undefined
 Volume dependence of LVH measurement31—optimal timing of LVH relative to dialytic schedule uncertain
 Ideal interval between repeated assessments undefined
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LVH-left ventricular hypertrophy. LVMI-left ventricular mass index. CV-cardiovascular

In summary, LVH is a promising target and the weight of evidence suggests that it is a modifiable risk factor in ESRD and that targeting LVH reduction may ultimately become the standard of care in ESRD. Nevertheless, at this time randomized, controlled studies are warranted to better define the optimal therapeutic approach to LVH and its suitability as a surrogate outcome measure before a clinical focus on LVH reduction can be widely advocated.

Key Points.

  • LVH is highly prevalent in individuals with ESRD

  • LVH is a risk factor for death in the ESRD population but may not be independently associated with outcomes.

  • Change in LVH over time is strongly associated with the risk of death during follow-up

  • Therapeutic trials have confirmed the feasibility of LVH regression but have not confirmed an association of change with improvement in survival

  • Additional evidence is needed before LVH reduction can be advocated as the standard of care

Acknowledgments

Dr. Charytan was supported by NIH grant 1U01DK096189-01.

Dr Charytan has received consulting and research support from Medtronic for a trial of invasive monitoring in chronic dialysis patients, consulting support from Keryx Biopharmaceuticals, and fee related legal review for Fresenius.

Abbreviations

LVH

left ventricular hypertrophy

LVMI

left ventricular mass index

CVD

cardiovascular disease

HD

hemodialysis

PD

peritoneal dialysis

HR

hazard ratio

CI

confidence interval

Footnotes

Conflicts of Interest: None.

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